I The insulin like-growth factor (IGF) system is well recognized to control mulfiple processes including growth, differentlafion, cancer and aging. Our preliminary data includes evidence that genefic variations in the GH- IGF system is involved in human longevity and that the IGF-IGFBP system is a potent modulator of cancer progression in vitro and In vivo. In this project, we propose to utilize an array of unique cell lines and mouse models we have established with focus on IGFBP-deficient mice to determine if they exhibit altered life span or altered stress responsiveness and survival in response to oxidative stress and chemotherapy and to see if fasting results in an additive or antagonistic stress response to toxins. We will also investigate the mechanisms responsible for IGFBP-dependent effects on stress resistance and will examine the differential stress response (DSR) effect in murine genetic models of prostate cancer mated into IGF/IGFBP modified strains. Finally, we plan to invesfigate if IGF modulafing drugs mimic or complement the DSR effects of fasting and diet on stress resistance and longevity in these models. The ulfimate goal of this project is to test the hypothesis that lGF-1 and IGFBPs play central roles in the modulafion of stress resistance as it relates to aging and diseases of aging. This knowledge can be applied to develop pharmacologic and nutrifional intervenfions that will protect older pafients against cancer, chemotherapy and radiotherapy, and other age- dependent diseases caused by endogenous toxins. We will therefore pursue the following specific aims: 1) Invesfigate the mechanism and differenfial action of IGFBPs on protection and sensifizafion of normal and transformed cells in vitro. Our hypothesis is that IGFBPs confer a differential stress resistance effect between primary and cancer cell lines through a dual mechanism involving both IGF-inhibition and direct cellular acfions. 2) Define the role of IGFBPs in longevity and in vivo stress resistance through the use of the IGFBPS and IGFBPl knockout mice. 3) Examine the effects of IGF-modulafing drugs including IGF-1 receptor blocking-anfibodies on stress resistance and longevity in mice. 4) Determine the effects of IGF and IGFBPs on survival in prostate cancer models by mafing IGF/IGFBP altered mice into genefic prostate cancer models, testing the progression of prostate cancer. Together, these studies will develop new strategies to understand the molecular mechanisms of cellular protection and apply them to differential protection of normal and cancer cells and the development of strategies to enhance healthy aging. RELEVANCE (See instructions); The insulin-like growth factor (IGF) system is a complex biological pathway that controls cellular and organismal growth and differenfiation; and has been linked to aging and longevity on one hand and to cancer progression on the other. We will address important implicafions of potenfial therapies that target IGF activity and examine their effects on lifespan and on cancer development in mouse models. Our work will have direct relevance to the health of elderly Americans, as it will pave the way towards safe and effective approaches to enhance lifespan and health-span extension and healthy aging.